The key role that immune responses play in obesity, development of insulin resistance and type 2 diabetes (T2D) has been acknowledged as a critical area of research with clinical importance. We have observed in small pilot studies, islet autoimmunity (islet autoantibodies and/or islet specific T cells) in T2D patients and have demonstrated islet autoimmunity to be associated with a more severe beta (?)-cell lesion, and a more rapid decline in ?-cell function. We hypothesize that Islet autoimmunity is an important contributor to the ?-cell functional decline in T2D and may impact the efficacy of diabetes therapies. We will perform our investigations within the framework of The Restoring Insulin Secretion (RISE) study. RISE is a large NIH supported clinical trial investigating medical and surgical interventions for the restoration and preservation of ?-cell function in pre-diabetes and early T2D. The prospective design of the RISE study provides an ideal opportunity to extend the results of our small pilot studies into a large longitudinally followed ethnically diverse cohort o T2D and pre-diabetes patients. To date, using internal funds, we have analyzed 74 baseline blood samples and 14 6-month samples for islet reactive T cells from RISE study subjects and have observed cellular islet autoimmunity in 40% of RISE patients (preliminary data). Funding of this proposal will allow us to continue collection and analysis of RISE patient samples for islet autoimmunity and begin investigating, with the assistance of our expert collaborators, additional immunological mechanisms associated with ?-cell functional decline identified in Type 1 (T1D) diabetes (circulating microRNA, peripheral immune signatures (immune phenotypes and cytokines), high affinity islet autoantibodies, and ? cell death (unmethylated INS DNA)) in the pathophysiology of T2D, and the impact of islet autoimmunity on the RISE interventions. Our access to RISE subjects, our proficiency in the use of the validated assays outlined in this ancillary study, and the expert assistance of our collaborators puts us in a unique position to accomplish our proposed research. The results of this ancillary study are likely to have a major impact on our understanding of the pathophysiology of the ?-cell dysfunction associated with T2D and may result in identification of immune based therapies beneficial for T2D patients.